Differentiated Thyroid Carcinoma: Risk Group Assignment and Management Controversies

Dr. Hicks and his associates have written an excellent article that summarizes current knowledge about the biologic behavior of differentiated carcinoma of the thyroid gland and explores current controversies related to its management. Their review is reasonably complete, citing most of the important recent references on the subject. Regarding treatment con- troversies, the authors discuss the differing philosophies of various investigators and place into perspective the data supporting these opposing viewpoints.

Aggressive vs Conservative Management

In general, differentiated carcinoma of the thyroid carries an excellent prognosis. Nevertheless, over the past 50 years, the clinical management of this disease has generated considerable debate. This debate is centered on whether an aggressive approach to treatment—namely, total thyroidectomy for all patients, coupled with elective lymph node dissection—is warranted, or whether a more conservative, selective approach is appropriate.

In the past, advocates of total thyroidectomy for all patients argued that the presence of multicentric foci in the thyroid gland is sufficient justification for the aggressive approach.[1] Proponents of lobectomy for unifocal lesions countered by stating that local recurrence rates in the opposite lobe following ipsilateral lobectomy are very low and do not differ significantly from recurrence rates following total thyroidectomy.[2] Similarly, supporters of aggressive treatment recommended elective dissection of regional lymph nodes in an effort to improve survival, whereas advocates of conservative management argued that even though the incidence of micrometastasis in clinically nonpalpable lymph nodes is as high as 50%, elective treatment of these micrometastases does not improve survival.

As Hicks et al point out, multivariate analysis has shown that multifocality and regional lymph node metastasis are not important prognostic factors in patients with differentiated thyroid cancer, except in those who are elderly.

Identification of Prognostic Factors

Identification of prognostic factors has significantly improved our understanding of the biologic behavior of this unique neoplasm. Although the tumor may look similar histologically in young and old patients, prognosis in these two age groups is completely different. In general, younger patients do very well regardless of the therapy they receive, whereas older patients do not do as well despite adequate treatment. So important is the impact of age on prognosis that differentiated thyroid carcinoma is the only cancer in which age is considered a factor in the American Joint Committee on Cancer (AJCC) clinical staging system.[3]

The definitive impact of age and other prognostic factors (tumor size, extrathyoidal extension, distant metastasis, and histology) has been confirmed by numerous reports from major US institutions, as well as a multi-institutional cooperative report of the European Organization for Research and Treatment of Cancer.[4] Further analysis of data based on an understanding of prognostic factors has enabled the development of risk-group stratification and use of these criteria for the selection of treatment. Clearly, such selectivity in choosing therapy not only will improve the survival of intermediate- and high-risk patients but also will reduce morbidity and treatment costs in low-risk patients.

Insights Into Histomorphology and Pathology

Insights into the histomorphologic features and pathologic behavior of differentiated thyroid cancers have also shed significant light on our understanding of these tumors. We now know, for example, that the evolution of a follicular adenoma into a follicular carcinoma is a continuum, which begins when a benign adenomatous lesion develops cellular atypia, leading to microinvasion of its capsule and minimal vascular invasion. By this process, a cellular adenoma progresses to a minimally invasive follicular carcinoma (the so-called nonfatal follicular carcinoma) with essentially no risk for distant dissemination.

Thus, as described by the authors, the difference between a minimally invasive (microinvasive) follicular carcinoma and histologically aggressive (macroinvasive) follicular cancer is clinically important. Using this histologic difference to guide treatment selection will avoid unnecessary aggressive treatment and thereby reduce morbidity in patients with minimally invasive carcinoma while enhancing the potential benefit of aggressive treatment in patients with macroinvasive follicular cancers.

Such clarification of the microscopic nature of follicular carcinoma also helps resolve a dilemma faced by surgeons in clinical practice: In this frequently encountered scenario, a thyroid nodule is found to be a unifocal nodule at surgical exploration and is treated by a lobectomy. The frozen section of the nodule is reported as “follicular adenoma” but the paraffin section is reported as “follicular carcinoma.” The immediate, but misguided, reaction of many clinicians would be to take the patient back to the operating room for a completion total thyroidectomy. Rather, the surgeon should review the surgical pathology with the pathologist. If the lesion is an aggressive (macroinvasive) follicular carcinoma, a completion total thyroidectomy is clearly justified. On the other hand, if the lesion proves to be a minimally invasive follicular cancer, there does not appear to be any rationale for completion total thyroidectomy.

Pathologic studies have also shown that a well-differentiated papillary or follicular carcinoma follows a continuous, albeit slow, process of evolution into an anaplastic carcinoma (Figure 1). The intermediate phase in this evolutionary process is man- ifested by the so-called poorly differentiated carcinoma of varying histologic grades,[5] a category that includes insular carcinoma and tall cell variant of cancer of the thyroid. Similarly, varying degrees of follicular and papillary histology may be identified in a given lesion. Thus, it is important to carefully review the pathology of the primary tumor before making a decision regarding aggressive surgical intervention or adjuvant therapy.

Conclusions

The issue of the aggressiveness of therapy for differentiated thyroid cancer is still relevant today. Diverse opinions on the clinical management of differentiated thyroid cancer are commonplace, due to the lack of appreciation of the importance of prognostic factors. A study of the patterns of care for differentiated thyroid carcinoma in the United States reported in 1995 by the American College of Surgeons found that a majority of patients undergo bilateral operations, while a sizable group are treated by ipsilateral lobectomy. However, there are no data showing a benefit of bilateral operations in all patients.[6]

At this juncture, it seems to be prudent to conclude that a detailed study of the pathology of the primary tumor and appropriate risk-group stratification of patients based on a consideration of prognostic factors are essential steps in the selection of appropriate treatment. Such a balanced approach allows the clinician to identify high-risk patients who are likely to benefit from aggressive surgical intervention and adjuvant therapy and spare low-risk patients the morbidity and cost of a more extensive operation and unnecessary adjuvant therapy. Such a selective treatment strategy will enhance the cost-effectiveness of therapy for patients with this neoplasm, the majority of whom fall into the low-risk category and have an excellent prognosis.

References:

1. Clarke RL, White EC, Russell WO: Total thyroidectomy for cancer of the thyroid: Significance of intraglandular dissemination. Ann Surg 149:858, 1959.

2. Tollefsen HR, Shah JP, Huvos AG: Papillary carcinoma of the thyroid. Am J Surg 1243:468-472, 1972.

3. Fleming ID, Cooper JS, Hutter RVP, et al (eds): AJCC Cancer Staging Manual, 5th ed, pp 59-64. Philadelphia, Lippincott-Raven, 1997.

4. Byar D, Green S, Dor P, et al: A prognostic index for thyroid carcinoma: A study of the EORTC Thyroid Cancer Cooperative Group. Eur J Cancer 15:1033-1041, 1979.

5. Rosai J, Carcangiu ML, DeLellis RA: Tumors of the thyroid gland, in Atlas of Tumor Pathology. AFIP, 1992.

6. Hundahl SA, Fleming I, Shah JP: Patterns of care for thyroid cancer, in National Cancer Data Base: Annual Review of Patient Care, pp 100-112. Atlanta, American Cancer Society, 1995.